Compartmentalization of integrin α6β4 signaling in lipid rafts

Gagnoux‐Palacios, Laurent; Dans, Michael; Hof, Wouter van’t; Mariotti, Agnese; Pepe, Angela; Meneguzzi, Guerríno; Resh, Marilyn D.; Giancotti, Filippo G.

doi:10.1083/jcb.200305006

Cited by 114 publications

(126 citation statements)

References 28 publications

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“…Therefore, it is possible that curcumin may affect one of the signaling pathways responsible for the phosphorylation of these Ser residues. Alternatively, palmitoylation of membrane proximal Cys residues of b4 integrin is required for lipid raft localization of a6b4 (20). On the basis of our data, which show that curcumin shifts a6b4 from lipid raft to nonlipid raft fractions (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Mobilization of a6b4 from HDs to leading edges of migrating carcinoma cells is thought to increase the localization of a6b4 into lipid rafts (16), where lots of other signaling receptors are located in the near vicinity so that a6b4 acts as a signal amplifier of these receptors (20,21,31). Therefore, we tested whether curcuminmediated a6b4 sequestration in HDs affects localization of a6b4 in lipid rafts (Fig.…”

Section: Curcumin Prevents Localization Of A6b4/egfr To Lipid Raftsmentioning

confidence: 99%

“…The localization of a6b4 to actin filament-rich structures such as lamellipodia and filopodia has an important implication for cancer cell motility and invasion, because integrins can harness traction forces through association with F-actin and their ability to engage the extracellular matrix (18,19). In addition, localization of a6b4 in the leading edge is thought to increase the level of a6b4 in lipid rafts (20). Lipid rafts are sphingolipid and cholesterol-rich microdomains of the plasma membrane (21,22).…”

Section: Introductionmentioning

confidence: 99%

“…Lipid rafts are sphingolipid and cholesterol-rich microdomains of the plasma membrane (21,22). Lipid rafts can act as "signaling platforms," in which signaling initiation and amplification occur more efficiently by recruiting signaling receptors into close proximity (20)(21)(22)(23). Once a6b4 localizes in lipid rafts, it is assumed that its signaling function is enhanced through interaction with other signaling receptors such as EGFR (20,21).…”

Section: Introductionmentioning

confidence: 99%

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Curcumin Inhibition of the Functional Interaction between Integrin α6β4 and the Epidermal Growth Factor Receptor

Soung

2011

Molecular Cancer Therapeutics

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The functional interaction between integrin a6b4 and growth factor receptors has been implicated in key signaling pathways important for cancer cell function. However, few attempts have been made to selectively target this interaction for therapeutic intervention. Previous studies showed that curcumin, a yellow pigment isolated from turmeric, inhibits integrin a6b4 signaling important for breast carcinoma cell motility and invasion, but the mechanism is not currently known. To address this issue, we tested the hypothesis that curcumin inhibits the functional interaction between a6b4 and the epidermal growth factor receptor (EGFR). In this study, we found that curcumin disrupts functional and physical interactions between a6b4 and EGFR, and blocks a6b4/EGFR-dependent functions of carcinoma cells expressing the signaling competent form of a6b4. We further showed that curcumin inhibits EGF-dependent mobilization of a6b4 from hemidesmosomes to the leading edges of migrating cells such as lammelipodia and filopodia, and thereby prevents a6b4 distribution to lipid rafts where functional interactions between a6b4 and EGFR occur. These data suggest a novel paradigm in which curcumin inhibits a6b4 signaling and functions by altering intracellular localization of a6b4, thus preventing its association with signaling receptors such as EGFR. Mol Cancer Ther; 10(5); 883-91. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Curcumin Prevents Localization Of A6b4/egfr To Lipid Raftsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Curcumin Inhibition of the Functional Interaction between Integrin α6β4 and the Epidermal Growth Factor Receptor

Soung

2011

Molecular Cancer Therapeutics

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“…Thus, galectin-3 might play an important role in the ternary complex formation in lipid rafts. Compartmentalization of lipid rafts is necessary to couple ␣6␤4 integrin and EGFR to active Src family kinase, which both prevents incorporation of ␣6␤4 integrin into hemidesmosomes and promotes cell migration (42,44,57). Some studies have reported that integrins are localized in the so-called glycosphingolipid-enriched microdomain rather than existing in lipid rafts on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Bisecting GlcNAc Residues on Laminin-332 Down-regulate Galectin-3-dependent Keratinocyte Motility

Kariya

Kawamura

Tabei

et al. 2010

Journal of Biological Chemistry

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(2008) J. Biol. Chem. 283, 33036 -33045). However, the underlying molecular mechanism by which GnT-III-Lm332 suppresses the normal biological functions of Lm332 remains to be elucidated. In this study, we show that galectin-3, which is a ␤-galactoside-binding protein, strongly bound to unmodified Lm332 but not to GnT-IIILm332 and that binding of galectin-3 was completely blocked by lactose. Exogenous galectin-3 significantly enhanced keratinocyte cell motility on control Lm332 but not on GnT-III-Lm332. A functional blocking antibody against galectin-3 inhibited Lm332-induced ␣3␤1 and ␣6␤4 integrin clustering and focal contact formation. Co-immunoprecipitation revealed that galectin-3 associated with both ␤4 integrin and epidermal growth factor receptor, thereby cross-linking the two molecules. The associations were inhibited by either the presence of lactose or expression of GnT-III. Moreover, galectin-3 consistently enhanced ERK activation. Taken together, the results of this study are the first to clearly identify the molecular mechanism responsible for the inhibitory effects of GnT-III on extracellular matrix-integrin-meditated cell adhesion, migration, and signal transduction. The findings presented herein shed light on the importance of N-glycosylation-mediated supramolecular complex formation on the cell surface.Tissue maintenance requires that cells be in communication with the surrounding microenvironment. During both physical and pathological conditions, cells receive extracellular matrix (ECM) 2 -mediated signals via cell surface receptors, including cell adhesion, migration, differentiation, and proliferation (1, 2). Significant research effort, using biochemical and genetic techniques, has advanced our understanding of how ECM signals are transduced and then translated into the cell. However, most studies have focused on the protein-protein interactions, namely on ECM-cell surface receptor interactions, rather than on carbohydrate-protein interactions.Laminin-332 (Lm332; previously known as laminin-5) is a component of basement membranes in the skin and other stratified squamous epithelial tissues (2-4). Lm332, which consists of ␣3, ␤3, and ␥2 subunits, associates with hemidesmosomes through integrin ␣6␤4 (5). A null mutation for Lm332 causes a severe and lethal skin blistering disease (6, 7). On the other hand, Lm332 is overexpressed at the leading edge of wounds during healing (8 -10) and in various types of squamous and other epithelial tumors (11,12). In addition, Lm332 plays an essential role in a mouse model of human squamous cell carcinoma tumorigenesis (13). Consistent with the result of in vivo studies, Lm332 promotes various cellular activities in vitro, such as cell adhesion, spreading, migration, and proliferation, via association of the carboxyl-terminal globular domain of the ␣3 chain with cell surface receptors, such as ␣3␤1 integrin, ␣6␤4 integrin, and syndecans (14 -16).Although between 13 and 30% of the total molecular weight of laminins is N-linked glycosylated (17), most studies o...

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Hemidesmosomes and their Components: Adhesion versus Signaling in Health and Disease

2008

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Compartmentalization of integrin α6β4 signaling in lipid rafts

Cited by 114 publications

References 28 publications

Curcumin Inhibition of the Functional Interaction between Integrin α6β4 and the Epidermal Growth Factor Receptor

Curcumin Inhibition of the Functional Interaction between Integrin α6β4 and the Epidermal Growth Factor Receptor

Bisecting GlcNAc Residues on Laminin-332 Down-regulate Galectin-3-dependent Keratinocyte Motility

Hemidesmosomes and their Components: Adhesion versus Signaling in Health and Disease

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